PROJECT SUMMARY/ABSTRACT: Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative brain disease, with language impairment as the primary feature. PPA is associated with two main classes of underlying neuropathology: Alzheimer's disease (AD) neuropathology and frontotemporal lobar degeneration (FTLD) neuropathology. Research advances, knowledge and interest in dementias due to FTLD have flourished over the past few years allowing for new dedicated resources (e.g., Advancing Research and Treatment for Frontotemporal Degeneration [ARTFL]), which promise exciting new opportunities for advancing our understanding the disease and for developing therapeutics. Unfortunately, individuals with PPA due to AD have been largely orphaned during this process; failing to meet pathologic inclusion criteria for FTLD studies and failing to meet clinical criteria for AD clinical trials, which tend to focus on individuals with the more typical amnestic phenotype. This is unfortunate because individuals with PPA due to AD represent up to 45% of all PPA cases and these individuals are potentially viable candidates for AD-related therapeutics. The proposed study will longitudinally and quantitatively characterize the clinical, cognitive, functional, neuroanatomic and molecular features of individuals with PPA who have biomarker findings consistent with AD (termed PPA-ADbio+ for this project). Aim 1a will quantitatively characterize longitudinal changes in morphometry (using structural MRI), functional connectivity (using resting state MRI), tau accumulation (with [18F]-AV-1451 Tau- PET) and clinical profiles (using detailed neuropsychological testing) of 50 PPA-ADbio+ participants at 3 consecutive annual visits. Aim 1b will characterize the temporal relationship among the variables measured in Aim 1a. This project represents one of the first prospective multidimensional studies of longitudinal course using the relatively new tau biomarker [18F]-AV-1451 in PPA-ADbio+ individuals. In addition to their theoretical interest, the results from this study are relevant for defining objective biomarkers of disease type and progression, which will inform therapeutic treatment strategies for this relatively underserved dementia population.